1. Field of the Invention
The present invention relates to ketomethionine ketals and hemiketals and derivatives thereof and their production and use as feed additives.
2. Description of the Background Art
Amino acids such as methionine, lysine or threonine are, as feed additives, important components of animal nutrition. They make possible more rapid growth and also more efficient feed utilization. This usually represents an important economic advantage. The markets for feed additives are of great industrial and economic importance. In addition, they are great growth markets which is due, not least, to the increasing importance of countries such as China and India, for example.
WO 2004008874 discloses, inter alia, that methionine is the first limiting amino acid for many animal species, including ruminants. For instance in the case of dairy cows, for example, efficient milk production with respect to the amount and quality is greatly dependent on a sufficient supply of methionine. The methionine requirement of high performance dairy cows cannot be covered in this case by the microbial protein formed in the rumen or by protein from the feed not degraded in the rumen (Graulet et al., J. Animal and Feed Sciences (2004), 269). It is therefore advantageous to supplement methionine to the feed to increase the economic efficiency of milk production and the quality of the milk.
In the case of monogastric animals such as, for example, poultry and pigs, customarily, as feed additive, use is made of methionine and the Methionine Hydroxy Analogue (MHA), which is also termed hydroxymethylthiobutyric acid (HMB). This increases the available amount of L-methionine in the body which can then be available to the animal for growth.
In contrast thereto, supplementation of the feed with methionine is ineffective in ruminants, since the majority is degraded by microbes in the rumen of ruminants. Owing to this degradation, therefore, only a fragment of the methionine supplemented passes into the small intestine of the animal, where generally the absorption of methionine into the blood proceeds.
WO 99/04647 describes the use of MHA for ruminants. Therein it is asserted that MHA is only in part broken down in the rumen and therefore at least 20-40% of the supplemented MHA, after absorption in the small intestine, can pass in to metabolism. In numerous other publications, in contrast, the mode of action of MHA in ruminants is discussed differently. For instance, WO 200028835, for example, describes that MHA can only successfully pass through the rumen and finally into the small intestine for absorption when MHA is administered in very large amounts of 60-120 g/day/animal. However this precludes economic efficiency.
In order that methionine products such as D,L-methionine or rac-MHA are available to ruminants with high efficiency, a form protected against rumen degradation must be used. The challenge in this case is to find a suitable methionine product which gives the methionine a rumen stability as high as possible and nevertheless ensures high and efficiency absorption of the methionine in the gut. There is a plurality of possibilities in this case of giving D,L-methionine or rac-MHA these properties:
a) Physical protection:
By application of a suitable protective layer or distribution of the methionine in a protective matrix, a high rumen stability can be achieved. As a result, the methionine can pass through the rumen virtually without loss. In its further course, the protective layer is then, for example, opened or removed by acid hydrolysis in the abomasum and the methionine released can then be absorbed by the animal in the small intestine. The protective layer or protective matrix can consist of a combination of a plurality of substances such as, for example, lipids, inorganic materials and carbohydrates. The following product forms are commercially available:
i) MET-PLUS™ from Nisso America is a lipid-protected methionine having a D,L-methionine content of 65%. The protective matrix consists of the calcium salts of long chain fatty acids such as, for example, lauric acid. As preservative, butylated hydroxytoluene is used.
ii) MEPRON® M85 from Degussa AG is a carbohydrate-protected methionine which has a core of D,L-methionine, starch and stearic acid. As protective layer, ethylcellulose is used. The product has a content of 85% D,L-methionine.
iii) SMARTAMINE™ M from Adisseo is a polymer-protected methionine. The pellets, in addition to stearic acid, contain at least 70% D,L-methionine. The protective layer contains vinylpyridine-styrene copolymer.
Although the physical protection prevents microbial breakdown of methionine in the rumen and as a result the supply and utilization of methionine in the animal can be increased, there are some serious disadvantages.
The production or coating of methionine is usually a technically complicated and laborious process and is therefore expensive. In addition the surface coating of the finished pellets can easily be damaged by mechanical load and abrasion during feed processing which can lead to reduction or up to complete loss of the protection. Therefore, it is also not possible to process and repellet the protected methionine pellets to form a larger compound feed pellet, since, as a result, again the protecting layer would break owing to the mechanical stress. This greatly restricts the use of such products, since compound feed pelleting is a widely used method of feed processing.
b) Chemical protection:
Increased rumen stability of methionine can, in addition to purely physical protective possibilities, also be achieved by modifying the chemical structure, for example by esterifying the carboxylic acid group. Currently, the following products are commercially available or are described in the literature:
i) Methionine esters such as, for example, D,L-tert-butylmethionine: The esters have been tested and demonstrated only moderate rumen stability (Loerch and Oke; “Rumen Protected Amino Acids in Ruminant Nutrition” in “Absorption and Utilization of Amino Acids” Vol. 3, 1989, 187-200, CRC Press, Boca Raton, Fla.). For D,L-tert-butylmethionine, in contrast, in WO 0028835, a biological value of 80% was published.
ii) METASMART™ from Adisseo is the racemic isopropyl ester of MHA (HMBi). This compound is also marketed under the trademark “Sequent” by the American company Novus. In WO 00/28835, a biological value of at least 50% for HMBi in ruminants was published. In this case, especially, the surprisingly rapid absorption of the hydrophobic HMBi through the rumen wall plays a decisive role. The ester can then be hydrolysed to MHA in the blood and, after oxidation and subsequent transamination, can be converted to L-methionine. In the patent EP 1358805, a comparable biological value for HMBi was published. In these studies, HMBi was applied to a porous support. In a further publication, the European Commission reported that, again, approximately 50% HMBi is absorbed via the rumen wall (European Commission: Report of the Scientific Committee on Animal Nutrition on the Use of HMBI; 25 Apr. 2003). Graulet et al. published in 2004 in the Journal of Animal and Feed Science (269), that better diffusion through the rumen wall is enabled by the lipophilic properties of the isopropyl group of HMBi.
For the production of HMBi, two different processes have been published. Thus, HMBi can either be synthesized directly in one stage from the corresponding cyanohydrin (WO 00-59877). Esterification to give the isopropyl ester proceeds in this case in situ, without needing to isolate MHA in advance. Another process, in contrast, esterifies pure MHA with isopropanol (WO 01-58864 and WO 01-56980). In both cases, for the synthesis, use is made of prussic acid which is expensive and in addition is a great potential hazard.
iii) Ketomethionine and its carboxylic acid derivatives: The use of this class of compounds, in particular of ketomethionine itself, as feed additives was first described recently in application WO 2006-072711. There, a technical process for producing ketomethionine and carboxylic acid derivatives thereof was also described. Ketomethionine is the direct precursor of methionine and can readily be converted in the body to L-methionine in one step by means of transamination. In comparison therewith, both MHA and HMBi have the disadvantage that they require two or three steps for conversion to L-methionine in the body. For instance, HMBi must first be hydrolysed to free MHA and subsequently oxidized to ketomethionine with the aid of an oxidase. Not until then can in turn the ketomethionine be directly reductively aminated to give L-methionine [Baker; “Utilization of Precursors for L-Amino Acids” in “Amino Acids in Farm Animal Nutrition” (D'Mello, J. P. F., ed.), 1994, 37-64. CAB Intl., Wallingford, Oxon, UK].
Free ketomethionine as α-ketocarboxylic acid and its salts such as, for example, the sodium or calcium salt, are compounds already known from the literature for a long time and have been produced both biochemically and chemically. Meister, for example, obtained the sodium salt of α-ketomethionine in a yield of 77% by the L-amino oxidase-catalysed oxidation of methionine (Meister, J. Biol. Chem. 1952, 197, 309). Previously, Waelsch et al., showed that the amino oxidases present in liver can convert methionine to α-ketomethionine (Waelsch et al., J. Am. Chem. Soc. 1938, 61, 2252). Mosbach et al., likewise described the production of ketomethionine by the L-amino oxidase-catalysed oxidation of methionine. In this case immobilized Providencia sp. PCM 1298 cells were used (Mosbach et al., Enzyme Microb. Technol. 1982, 4, 409).
As a further possible synthesis method, Sakurai et al. in 1957 published the first chemical synthesis route for synthesising α-ketomethionine. In this case, as key step, methyl-α-methoxalyl-γ-methylmercaptopropionate was hydrolyzed with dilute hydrochloric acid to give ketomethionine (Sakurai et al., J. of Biochemistry 1957, 44, 9, 557). Yamada et al. published virtually simultaneously the same synthesis route, after first attempts at synthesizing α-ketomethionine via an α-oximo ester formed as an intermediate gave only low yields. (Chibata et al., Bull. Agr. Chem. Soc. Japan 1957, 21, 6, 336).
The biological value of the sodium salt of α-ketomethionine was determined for the first time in 1977 in feeding experiments with rodents and poultry and is significantly above that of MHA (Baker and Harter, Proceedings for the Society for Experimental Biology and Medicine 1977, 156, 2001). In ruminants, α-ketomethionine and salts thereof, however, are broken down in the rumen and therefore offer no advantages over HMBi or methionine. As free α-ketocarboxylic acid, α-ketomethionine in addition has the further disadvantage that it dimerizes in a very short time and subsequently irreversibly cyclizes and therefore is not stable as a monomer of biological value and therefore is avoided in direct use as feed additive.